1.Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study
Hee Jo HAN ; Seung Woo KIM ; Hyunjin KIM ; Jungmin SO ; Eun-Jae LEE ; Young-Min LIM ; Jung Hwan LEE ; Myung Ah LEE ; Byung-Jo KIM ; Seol-Hee BAEK ; Hyung-Soo LEE ; Eunhee SOHN ; Sooyoung KIM ; Jin-Sung PARK ; Minsung KANG ; Hyung Jun PARK ; Byeol-A YOON ; Jong Kuk KIM ; Hung Youl SEOK ; Sohyeon KIM ; Ju-Hong MIN ; Yeon Hak CHUNG ; Jeong Hee CHO ; Jee-Eun KIM ; Seong-il OH ; Ha Young SHIN
Journal of Korean Medical Science 2024;39(18):e150-
Background:
During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea.
Methods:
This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients.
Results:
Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients.
Conclusion
This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.
2.Guideline for the Surgical Management of Locally Invasive Differentiated Thyroid Cancer From the Korean Society of Head and Neck Surgery
Jun-Ook PARK ; Joo Hyun KIM ; Young Hoon JOO ; Sang-Yeon KIM ; Geun-Jeon KIM ; Hyun Bum KIM ; Dong-Hyun LEE ; Hyun Jun HONG ; Young Min PARK ; Eun-Jae CHUNG ; Yong Bae JI ; Kyoung Ho OH ; Hyoung Shin LEE ; Dong Kun LEE ; Ki Nam PARK ; Myung Jin BAN ; Bo Hae KIM ; Do Hun KIM ; Jae-Keun CHO ; Dong Bin AHN ; Min-Su KIM ; Jun Girl SEOK ; Jeon Yeob JANG ; Hyo Geun CHOI ; Hee Jin KIM ; Sung Joon PARK ; Eun Kyung JUNG ; Yeon Soo KIM ; Yong Tae HONG ; Young Chan LEE ; Ho-Ryun WON ; Sung-Chan SHIN ; Seung-Kuk BAEK ; Soon Young KWON
Clinical and Experimental Otorhinolaryngology 2023;16(1):1-19
The aim of this study was to develop evidence-based recommendations for determining the surgical extent in patients with locally invasive differentiated thyroid cancer (DTC). Locally invasive DTC with gross extrathyroidal extension invading surrounding anatomical structures may lead to several functional deficits and poor oncological outcomes. At present, the optimal extent of surgery in locally invasive DTC remains a matter of debate, and there are no adequate guidelines. On October 8, 2021, four experts searched the PubMed, Embase, and Cochrane Library databases; the identified papers were reviewed by 39 experts in thyroid and head and neck surgery. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the quality of evidence, and to develop and report recommendations. The strength of a recommendation reflects the confidence of a guideline panel that the desirable effects of an intervention outweigh any undesirable effects, across all patients for whom the recommendation is applicable. After completing the draft guidelines, Delphi questionnaires were completed by members of the Korean Society of Head and Neck Surgery. Twenty-seven evidence-based recommendations were made for several factors, including the preoperative workup; surgical extent of thyroidectomy; surgery for cancer invading the strap muscles, recurrent laryngeal nerve, laryngeal framework, trachea, or esophagus; and surgery for patients with central and lateral cervical lymph node involvement. Evidence-based guidelines were devised to help clinicians make safer and more efficient clinical decisions for the optimal surgical treatment of patients with locally invasive DTC.
3.2023 Korean Thyroid Association Management Guidelines for Patients with Thyroid Nodules
Young Joo PARK ; Eun Kyung LEE ; Young Shin SONG ; Soo Hwan KANG ; Bon Seok KOO ; Sun Wook KIM ; Dong Gyu NA ; Seung-Kuk BAEK ; So Won OH ; Min Kyoung LEE ; Sang-Woo LEE ; Young Ah LEE ; Yong Sang LEE ; Ji Ye LEE ; Dong-Jun LIM ; Leehi JOO ; Yuh-Seog JUNG ; Chan Kwon JUNG ; Yoon Young CHO ; Yun Jae CHUNG ; Won Bae KIM ; Ka Hee YI ; Ho-Cheol KANG ; Do Joon PARK
International Journal of Thyroidology 2023;16(1):1-31
Thyroid nodules are a prevalent condition that can be detected through palpation or ultrasound. However, a small fraction of these nodules can be cancerous, and even benign nodules can cause symptoms if they grow and compress surrounding tissue. As such, it is important to monitor thyroid nodules and determine appropriate treatment options. In recent years, there has been a shift towards enhancing diagnostic accuracy and less aggressive treatment options. As a result, there is a growing need for the development of appropriate recommendations for their clinical application to ensure optimal patient outcomes. The present clinical practice guideline was developed by extracting the nodule section from the prior version of guidelines and updating it to fit the Korean circumstances. Task force members reviewed relevant studies selected after electronic database searching, and the recommendations are provided with a level of recommendation for each section. The revised guideline includes recommendations for thyroid cancer screening in high-risk groups, appropriate diagnostic methods for thyroid nodules, the role of pathological and molecular marker tests in diagnosis, long-term follow-up and treatment of benign thyroid nodules, and special considerations for pregnant women. The major changes in this revision are the definition of high-risk groups for thyroid cancer screening, the application of the revised Korean Thyroid Imaging Reporting and Data System (K-TIRADS), the addition of the role of core needle biopsy and molecular marker tests, the application of active surveillance in low-risk papillary thyroid microcarcinoma, and updated indications for non-surgical treatment of benign thyroid nodules. These evidence-based recommendations are expected to assist in clinical decision-making for thyroid nodule management, ensuring that patients receive the most appropriate and effective treatment options.
4.Multicenter Analysis of Clinical Features and Prognosis of COVID-19 Patients with Hepatic Impairment
Jeong Eun SONG ; Min Kyu KANG ; Yu Rim LEE ; Chang Hyeong LEE ; Jung Gil PARK ; Young Oh KWEON ; Won Young TAK ; Soo Young PARK ; Se Young JANG ; Jae Seok HWANG ; Byoung Kuk JANG ; Won Young JANG ; Jeong Ill SUH ; Woo Jin CHUNG ; Byung Seok KIM ;
Gut and Liver 2021;15(4):606-615
Background/Aims:
Recent data indicate the presence of liver enzyme abnormalities in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the clinical features and treatment outcomes of COVID-19 patients with abnormal liver enzymes.
Methods:
We performed a retrospective, multicenter study of 874 COVID-19 patients admitted to five tertiary hospitals from February 20 to April 14, 2020. Data on clinical features, laboratory parameters, medications, and treatment outcomes were collected until April 30, 2020, and compared between patients with normal and abnormal aminotransferases.
Results:
Abnormal aminotransferase levels were observed in 362 patients (41.1%), of which 94 out of 130 (72.3%) and 268 out of 744 (36.0%) belonged to the severe and non-severe COVID-19 categories, respectively. The odds ratios (95% confidence interval) for male patients, patients with a higher body mass index, patients with severe COVID-19 status, and patients with lower platelet counts were 1.500 (1.029 to 2.184, p=0.035), 1.097 (1.012 to 1.189, p=0.024), 2.377 (1.458 to 3.875, p=0.001), and 0.995 (0.993 to 0.998, p>0.001), respectively, indicating an independent association of these variables with elevated aminotransferase levels. Lopinavir/ ritonavir and antibiotic use increased the odds ratio of abnormal aminotransferase levels after admission (1.832 and 2.646, respectively, both p<0.05). The median time to release from quarantine was longer (22 days vs 26 days, p=0.001) and the mortality rate was higher (13.0% vs 2.9%, p<0.001) in patients with abnormal aminotransferase levels.
Conclusions
Abnormal aminotransferase levels are common in COVID-19 patients and are associated with poor clinical outcomes. Multivariate analysis of patients with normal aminotransferase levels on admission showed that the use of lopinavir/ritonavir and antibiotics was associated with abnormal aminotransferase levels; thus, careful monitoring is needed.
5.Survival Benefits From Surgery for Stage IVa Head and Neck Squamous Cell Carcinoma: A Multi-Institutional Analysis of 1,033 Cases
Jun-Ook PARK ; Young Min PARK ; Woo-Jin JEONG ; Yoo Seob SHIN ; Yong Tae HONG ; Ik Joon CHOI ; Ji Won KIM ; Seung Hoon WOO ; Yeon Soo KIM ; Jae Won CHANG ; Min-Sik KIM ; Kwang-Yoon JUNG ; Soon-Hyun AHN ; Chul-Ho KIM ; Ki Hwan HONG ; Phil-Sang CHUNG ; Young-Mo KIM ; Se-Heon KIM ; Seung-Kuk BAEK
Clinical and Experimental Otorhinolaryngology 2021;14(2):225-234
Objectives:
. Head and neck squamous cell carcinomas (HNSCs) are frequently diagnosed at the locoregional advanced stage (stage IVa), but controversy remains regarding whether stage IVa HSNCs should be treated with upfront surgery or definitive chemoradiation therapy (CRT). The purpose of this study was to compare overall survival (OS) and disease-free survival (DFS) in patients with stage IVa HNSC treated primarily by surgery with curative intent with/without (neo)adjuvant treatment (surgery group) versus those treated primarily with CRT (CRT group).
Methods:
. We reviewed data of 1,033 patients with stage IVa HNSC treated with curative intent at 17 cancer centers between 2010 and 2016.
Results:
. Among 1,033 patients, 765 (74.1%) received upfront surgery and 268 (25.9%) received CRT. The 5-year OS and DFS rates were 64.4% and 62.0% in the surgery group and 49.5% and 45.4% in the CRT group, respectively. In multivariate analyses, OS and DFS were better in the surgery group than in the CRT group (odds ratio [OR] for death, 0.762; 95% confidence interval [CI], 0.592–0.981; OR for recurrence, 0.628; 95% CI, 0.492–0.802). In subgroup analyses, the OS and DFS of patients with oropharyngeal cancer were better in the surgery group (OR for death, 0.548; 95% CI, 0.341–0.879; OR for recurrence, 0.598; 95% CI, 0.377–0.948). In the surgery group, patients with laryngeal cancer showed better OS (OR for death, 0.432; 95% CI, 0.211–0.882), while those with hypopharyngeal cancer DFS was improved (OR for recurrence, 0.506; 95% CI, 0.328–0.780).
Conclusion
. A survival benefit from surgery may be achieved even in patients with stage IVa HNSC, particularly those with oropharyngeal and laryngeal cancer. Surgery led to a reduction in the recurrence rate in patients with hypopharyngeal cancer.
6.Survival Benefits From Surgery for Stage IVa Head and Neck Squamous Cell Carcinoma: A Multi-Institutional Analysis of 1,033 Cases
Jun-Ook PARK ; Young Min PARK ; Woo-Jin JEONG ; Yoo Seob SHIN ; Yong Tae HONG ; Ik Joon CHOI ; Ji Won KIM ; Seung Hoon WOO ; Yeon Soo KIM ; Jae Won CHANG ; Min-Sik KIM ; Kwang-Yoon JUNG ; Soon-Hyun AHN ; Chul-Ho KIM ; Ki Hwan HONG ; Phil-Sang CHUNG ; Young-Mo KIM ; Se-Heon KIM ; Seung-Kuk BAEK
Clinical and Experimental Otorhinolaryngology 2021;14(2):225-234
Objectives:
. Head and neck squamous cell carcinomas (HNSCs) are frequently diagnosed at the locoregional advanced stage (stage IVa), but controversy remains regarding whether stage IVa HSNCs should be treated with upfront surgery or definitive chemoradiation therapy (CRT). The purpose of this study was to compare overall survival (OS) and disease-free survival (DFS) in patients with stage IVa HNSC treated primarily by surgery with curative intent with/without (neo)adjuvant treatment (surgery group) versus those treated primarily with CRT (CRT group).
Methods:
. We reviewed data of 1,033 patients with stage IVa HNSC treated with curative intent at 17 cancer centers between 2010 and 2016.
Results:
. Among 1,033 patients, 765 (74.1%) received upfront surgery and 268 (25.9%) received CRT. The 5-year OS and DFS rates were 64.4% and 62.0% in the surgery group and 49.5% and 45.4% in the CRT group, respectively. In multivariate analyses, OS and DFS were better in the surgery group than in the CRT group (odds ratio [OR] for death, 0.762; 95% confidence interval [CI], 0.592–0.981; OR for recurrence, 0.628; 95% CI, 0.492–0.802). In subgroup analyses, the OS and DFS of patients with oropharyngeal cancer were better in the surgery group (OR for death, 0.548; 95% CI, 0.341–0.879; OR for recurrence, 0.598; 95% CI, 0.377–0.948). In the surgery group, patients with laryngeal cancer showed better OS (OR for death, 0.432; 95% CI, 0.211–0.882), while those with hypopharyngeal cancer DFS was improved (OR for recurrence, 0.506; 95% CI, 0.328–0.780).
Conclusion
. A survival benefit from surgery may be achieved even in patients with stage IVa HNSC, particularly those with oropharyngeal and laryngeal cancer. Surgery led to a reduction in the recurrence rate in patients with hypopharyngeal cancer.
7.Multicenter Analysis of Clinical Features and Prognosis of COVID-19 Patients with Hepatic Impairment
Jeong Eun SONG ; Min Kyu KANG ; Yu Rim LEE ; Chang Hyeong LEE ; Jung Gil PARK ; Young Oh KWEON ; Won Young TAK ; Soo Young PARK ; Se Young JANG ; Jae Seok HWANG ; Byoung Kuk JANG ; Won Young JANG ; Jeong Ill SUH ; Woo Jin CHUNG ; Byung Seok KIM ;
Gut and Liver 2021;15(4):606-615
Background/Aims:
Recent data indicate the presence of liver enzyme abnormalities in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the clinical features and treatment outcomes of COVID-19 patients with abnormal liver enzymes.
Methods:
We performed a retrospective, multicenter study of 874 COVID-19 patients admitted to five tertiary hospitals from February 20 to April 14, 2020. Data on clinical features, laboratory parameters, medications, and treatment outcomes were collected until April 30, 2020, and compared between patients with normal and abnormal aminotransferases.
Results:
Abnormal aminotransferase levels were observed in 362 patients (41.1%), of which 94 out of 130 (72.3%) and 268 out of 744 (36.0%) belonged to the severe and non-severe COVID-19 categories, respectively. The odds ratios (95% confidence interval) for male patients, patients with a higher body mass index, patients with severe COVID-19 status, and patients with lower platelet counts were 1.500 (1.029 to 2.184, p=0.035), 1.097 (1.012 to 1.189, p=0.024), 2.377 (1.458 to 3.875, p=0.001), and 0.995 (0.993 to 0.998, p>0.001), respectively, indicating an independent association of these variables with elevated aminotransferase levels. Lopinavir/ ritonavir and antibiotic use increased the odds ratio of abnormal aminotransferase levels after admission (1.832 and 2.646, respectively, both p<0.05). The median time to release from quarantine was longer (22 days vs 26 days, p=0.001) and the mortality rate was higher (13.0% vs 2.9%, p<0.001) in patients with abnormal aminotransferase levels.
Conclusions
Abnormal aminotransferase levels are common in COVID-19 patients and are associated with poor clinical outcomes. Multivariate analysis of patients with normal aminotransferase levels on admission showed that the use of lopinavir/ritonavir and antibiotics was associated with abnormal aminotransferase levels; thus, careful monitoring is needed.
8.Changes in Characteristics of Patients with Liver Cirrhosis Visiting a Tertiary Hospital over 15 Years: a Retrospective Multi-Center Study in Korea
Won Young JANG ; Woo Jin CHUNG ; Byoung Kuk JANG ; Jae Seok HWANG ; Heon Ju LEE ; Moon Joo HWANG ; Young Oh KWEON ; Won Young TAK ; Soo Young PARK ; Su Hyun LEE ; Chang Hyeong LEE ; Byung Seok KIM ; Si Hye KIM ; Jeong Ill SUH ; Jun Gi PARK
Journal of Korean Medical Science 2020;35(29):e233-
Background:
Liver cirrhosis has become a heavy burden not only for patients, but also for our society. However, little is known about the recent changes in clinical outcomes and characteristics of patients with cirrhosis-related complications in Korea. Therefore, we aimed to evaluate changes in characteristics of patients with liver cirrhosis in Daegu-Gyeongbuk province in Korea over the past 15 years.
Methods:
We retrospectively reviewed the medical records of 15,716 liver cirrhotic patients from 5 university hospitals in Daegu-Gyeongbuk province from 2000 to 2014. The Korean Standard Classification of Diseases-6 code associated with cirrhosis was investigated through medical records and classified according to the year of first visit.
Results:
A total of 15,716 patients was diagnosed with cirrhosis. A number of patients newly diagnosed with cirrhosis has decreased each year. In 2000, patients were most likely to be diagnosed with hepatitis B virus (HBV) cirrhosis, followed by alcoholic cirrhosis. There was a significant decrease in HBV (P < 0.001), but alcohol, hepatitis C virus (HCV), and non-alcoholic fatty liver disease (NAFLD) showed a significant increase during the study period (alcohol, P = 0.036; HCV, P = 0.001; NAFLD, P = 0.001). At the time of initial diagnosis, the ratio of Child-Turcotte-Pugh (CTP) class A gradually increased from 23.1% to 32.9% (P < 0.001). The most common cause of liver-related hospitalization in 2000 was hepatocellular carcinoma (HCC) (25.5%); in 2014, gastrointestinal bleeding with esophageal and gastric varices (21.4%) was the most common cause. Cases of hospitalization with liver-related complication represented 76.4% of all cases in 2000 but 70.9% in 2014. Incidence rate of HCC has recently increased. In addition, HCC-free survival was significantly lower in CTP class A than in classes B and C. Finally, there was significant difference in HCC occurrence according to causes (P < 0.001). HBV and HCV cirrhosis had lower HCC-free survival than alcoholic and NAFLD cirrhosis.
Conclusion
In recent years, the overall number of cirrhosis patients has decreased. This study confirmed the recent trend in decrease of cirrhosis, especially of cirrhosis due to HBV, and the increase of HCV, alcoholic and NAFLD cirrhosis. Targeted screening for at-risk patients will facilitate early detection of liver diseases allowing effective intervention and may have decreased the development of cirrhosis and its complications.
9.Clinical outcomes of coronavirus disease 2019 in patients with pre-existing liver diseases: A multicenter study in South Korea
Yu Rim LEE ; Min Kyu KANG ; Jeong Eun SONG ; Hyun Jung KIM ; Young Oh KWEON ; Won Young TAK ; Se Young JANG ; Jung Gil PARK ; Changhyeong LEE ; Jae Seok HWANG ; Byoung Kuk JANG ; Jeong Ill SUH ; Woo Jin CHUNG ; Byung Seok KIM ; Soo Young PARK
Clinical and Molecular Hepatology 2020;26(4):562-576
Background/Aims:
Although coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, the implication of pre-existing liver disease on the outcome of COVID-19 remains unresolved.
Methods:
A total of 1,005 patients who were admitted to five tertiary hospitals in South Korea with laboratory-confirmed COVID-19 were included in this study. Clinical outcomes in COVID-19 patients with coexisting liver disease as well as the predictors of disease severity and mortality of COVID-19 were assessed.
Results:
Of the 47 patients (4.7%) who had liver-related comorbidities, 14 patients (1.4%) had liver cirrhosis. Liver cirrhosis was more common in COVID-19 patients with severe pneumonia than in those with non-severe pneumonia (4.5% vs. 0.9%, P=0.006). Compared to patients without liver cirrhosis, a higher proportion of patients with liver cirrhosis required oxygen therapy; were admitted to the intensive care unit; had septic shock, acute respiratory distress syndrome, or acute kidney injury; and died (P<0.05). The overall survival rate was significantly lower in patients with liver cirrhosis than in those without liver cirrhosis (log-rank test, P=0.003). Along with old age and diabetes, the presence of liver cirrhosis was found to be an independent predictor of severe disease (odds ratio, 4.52; 95% confidence interval [CI], 1.20–17.02;P=0.026) and death (hazard ratio, 2.86; 95% CI, 1.04–9.30; P=0.042) in COVID-19 patients.
Conclusions
This study suggests liver cirrhosis is a significant risk factor for COVID-19. Stronger personal protection and more intensive treatment for COVID-19 are recommended in these patients.
10.Daclatasvir and asunaprevir combination therapy for patients with chronic hepatitis C virus genotype 1b infection in real world
Jae Young OH ; Byung Seok KIM ; Chang Hyeong LEE ; Jeong Eun SONG ; Heon Ju LEE ; Jung Gil PARK ; Jae Seok HWANG ; Woo Jin CHUNG ; Byoung Kuk JANG ; Young Oh KWEON ; Won Young TAK ; Soo Young PARK ; Se Young JANG ; Jeong Ill SUH ; Sang Gyu KWAK
The Korean Journal of Internal Medicine 2019;34(4):794-801
BACKGROUND/AIMS:
Previous studies have reported a high rate of sustained virologic response (SVR) and a low rate of serious adverse events with the use of daclatasvir (DCV) and asunaprevir (ASV) combination therapy. We evaluated the efficacy and safety of DCV and ASV combination therapy for patients with chronic hepatitis C virus (HCV) genotype 1b infection in real world.
METHODS:
We enrolled 278 patients (184 treatment-naïve patients) from five hospitals in Daegu and Gyeongsangbuk-do. We evaluated the rates of rapid virologic response (RVR), end-of-treatment response (ETR), and SVR at 12 weeks after completion of treatment (SVR12). Furthermore, we investigated the rate of adverse events and predictive factors of SVR12 failure.
RESULTS:
The mean age of patients was 59.5 ± 10.6 years, and 140 patients (50.2%) were men. Seventy-seven patients had cirrhosis. Baseline information regarding nonstructural protein 5A (NS5A) sequences was available in 268 patients. Six patients presented with pretreatment NS5A resistance-associated variants. The RVR and the ETR rates were 96.6% (258/267) and 95.2% (223/232), respectively. The overall SVR12 rate was 91.6% (197/215). Adverse events occurred in 17 patients (7.9%). Six patients discontinued treatment because of liver enzyme elevation (n = 4) and severe nausea (n = 2). Among these, four achieved SVR12. Other adverse events observed were fatigue, headache, diarrhea, dizziness, loss of appetite, skin rash, and dyspnea. Univariate analysis did not show significant predictive factors of SVR12 failure.
CONCLUSIONS
DCV and ASV combination therapy showed high rates of RVR, ETR, and SVR12 in chronic HCV genotype 1b-infected patients in real world and was well tolerated without serious adverse events.

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